Complement deficiencies Notes

NOTES NOTES COMPLEMENT DEFICIENCIES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Genetic diseases: a protein of the 30+ in complement system missing → abnormal inflammatory/immune response-prone individual SIGNS & SYMPTOMS ▪ Recurrent bacterial infection (i.e. pneumonia, tonsillitis, otitis), especially encapsulated bacteria ▪ Rheumatologic/autoimmune disorders ▫ Can be systemic lupus erythematosus (SLE)-like (fever, rash, arthritis, glomerulonephritis) DIAGNOSIS LAB RESULTS ▪ Screening based on recurrent infection/ autoimmune familial/individual history ▫ Genetic screening ▫ Total hemolytic complement (THC/ CH50) testing < 11% (measures individual serum’s ability to lyse sheep red blood cells (RBCs) coated with antiRBC rabbit antibody → activates serum complement proteins; AH50 alternative pathway evaluation test) 190 OSMOSIS.ORG ▪ Complement component serum levels ▫ Level ↓ correlates with specific protein deficiency ▫ Overactive pathway consumption → protein level ↓ (i.e. decreased C2/ C4 ↓ indicates classical pathway overactivation—as in C1 inhibitor deficiency) TREATMENT MEDICATIONS ▪ Bacterial infection prevention: vaccination ▫ Meningococcal, pneumococcal, Haemophilus influenzae b (Hib) vaccines (conjugated vaccines preferred for Hib pneumococcal) ▪ Bacterial infection-suspicious symptoms → swift antibiotic management

Chapter 31 Complement Deficiencies C1 ESTERASE INHIBITOR DEFICIENCY osms.it/complement_deficiency PATHOLOGY & CAUSES ▪ Autosomal dominant disorder: C1 inhibitor protein missing → clinical hereditary angioedema (HAE) syndrome ▪ C1 esterase inhibitor role: inhibits C1 protein cleavage in complement cascade ▫ C1 esterase inhibitor deficiency → overactive C1 cleavage → ↑ classical complement pathway activation → proinflammatory, ↑ immune responsive state → ↑ downstream anaphylatoxin production (C2a, C4a) ▪ C1 esterase inhibitor also mediates bradykinin production → hereditary angioedema (HAE) ▫ C1 esterase inhibitor absence → ↑ kallikrein, factor XII → unchecked bradykinin production → vasodilation → severe angioedema SIGNS & SYMPTOMS Angioedema episodes ▪ Commonly last 24–72 hours, without urticaria/pruritis ▫ Frequent prodromal symptoms: fatigue, nausea, gastrointestinal (GI) symptoms, myalgias present ▫ Individuals may report stress (physical/ mental) as episode triggers Edematous episodes ▪ Nondependent areas, non-pitting ▫ Most common locations: upper respiratory/GI tract skin/mucosal tissue ▫ GI bowel edema → nonspecific GI distress symptoms (abdominal pain, colic) ▫ Laryngeal edema most feared → closed airway → asphyxiation DIAGNOSIS LAB RESULTS ▪ Low C1 esterase inhibitor, C4 levels OTHER DIAGNOSTICS History ▪ Recurrent, self-resolving angioedema episodes with/without colicky, abdominal pain ▪ No concurrent angiotensin-converting enzyme (ACE) inhibitors/nonsteroidal antiinflammatory drug (NSAIDs) use ▪ Positive angioedema family history Physical examination ▪ Nondependent (i.e. head/neck), non-pitting edema areas without urticaria/pruritis TREATMENT MEDICATIONS ▪ Therapies: purified C1 inhibitor concentrate, kallikrein inhibitor, bradykinin-B2-receptor antagonist ▪ If above targeted therapy interventions unavailable → fresh frozen plasma ▪ Avoid angiotensin-converting-enzyme (ACE) inhibitors SURGERY ▪ Acute episodes → intubation for airway management OSMOSIS.ORG 191

C2 DEFICIENCY osms.it/complement_deficiency PATHOLOGY & CAUSES ▪ Autosomal recessive disorder: involves C2 protein absence in classical complement cascade ▫ Most common complement deficiency disorder ▫ Symptoms commonly present in early childhood ▪ Associated with IgG deficiency SIGNS & SYMPTOMS ▪ Individuals sometimes present with SLElike symptoms ▫ Fever, rash, arthritis, glomerulonephritis ▪ ↑ infection risk from encapsulated bacteria ▫ Streptococcus pneumoniae, Haemophilus influenza type b, Neisseria meningitidis DIAGNOSIS LAB RESULTS ▪ Recurrent SLE-like episodes: CH50 testing OTHER DIAGNOSTICS ▪ Clinical/family recurrent, bacterial infection history TREATMENT MEDICATIONS ▪ Bacterial infection vigilance: prompt antibiotic therapy ▪ SLE-like episodes: corticosteroids, other immunosuppressants C3 DEFICIENCY osms.it/complement_deficiency PATHOLOGY & CAUSES ▪ Autosomal recessive disorder: involving protein C3 (vital protein connecting three complement activation pathways— classical, alternative, lectin—to final, common pathway) ▫ Presents with severe infections shortly after birth ▫ Rarest complement deficiency disorder ▪ Cleavage product: C3b (major opsonin) ▫ Inability to effectively opsonize without C3b → antigen-antibody complex unable to be phagocytosed → excess immune complex formation, deposition 192 OSMOSIS.ORG → type III hypersensitivity reaction ▫ Inability to opsonize underlies frequently encountered sinopulmonary diseases (see bacterial infections below) ▪ Inability to form C5 convertase → deficient membrane attack complex (MAC) formation ▫ Inability to complete complement cascade underlies (primarily meningitisrelated) septic presentation ▪ Abnormal C3 protein levels → abnormal three complement pathway activation → abnormal pathway byproduct concentrations (i.e. anaphylatoxins C2a, C4a) → abnormal immune cell response to immune insult → abnormal neutrophil response → abscess formation

Chapter 31 Complement Deficiencies SIGNS & SYMPTOMS ▪ Severe, recurrent encapsulated bacterial infections shortly after birth ▫ Particularly Streptococcus pneumoniae ▪ Children who survive severe infections develop problems secondary to immune complex deposition, reaction ▫ Especially membranoproliferative glomerulonephritis TREATMENT MEDICATIONS ▪ Bacterial infection vigilance: prompt antibiotic therapy ▪ Bacterial infection prophylaxis: vaccination ▫ Pneumococcal vaccination ▫ Meningococcal vaccination (for resulting dysfunctional C5–C9 MAC formation) DIAGNOSIS LAB RESULTS ▪ Clinical/family history of recurrent, bacterial infections (especially Streptococcus pneumoniae) → CH50 testing C5-C9 DEFICIENCY osms.it/complement_deficiency PATHOLOGY & CAUSES DIAGNOSIS ▪ Autosomal recessive disorder group: involving any protein (C5–C9) involved in MAC formation (part of final, common complement pathway) ▪ MAC-forming inability: precludes ability to create osmotic gradient for cellular lysis LAB RESULTS SIGNS & SYMPTOMS MEDICATIONS ▪ Frequent, recurrent bacterial infection ▫ Propensity for Neisseria gonorrhoeae, meningitidis infections (thin cell walls → especially complement destructionvulnerable) ▪ Clinical recurrent, bacterial infection history (especially Neisseria species) → CH50 testing TREATMENT ▪ Bacterial infection vigilance: prompt antibiotic therapy ▪ Severe bacterial infection mitigation: meningococcal vaccination OSMOSIS.ORG 193

PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) osms.it/pnh PATHOLOGY & CAUSES ▪ Acquired genetic disorder: hematopoietic stem cells produce cells that lack cellmembrane protein CD55 (AKA decayaccelerating factor (DAF)) or CD59 that predispose cells to complement-mediated lysis ▫ Involved gene (on X chromosome) is phosphatidylinositol glycan complementation group A (PIGA) ▫ Biologically-male individuals in early 20s (most common) ▪ CD59: anchor protein for glycosylphosphatidylinositol (GPI), a marker of ‘self’ antigenicity on erythrocytes, leukocytes ▫ CD59 deficiency → cells sensitive to complement-mediated lysis → intravascular hemolysis ▫ Nocturnal: relative hypoventilation during sleep → slightly ↑ serum CO2 → slightly acidic serum pH → ↑ complement activity → ↑ nighttime hemolysis COMPLICATIONS ▪ Potentially fatal venous (Budd–Chiari syndrome), arterial thrombosis ▪ Aplastic anemia, myelodysplasia, myelofibrosis, acute leukemia evolution SIGNS & SYMPTOMS ▪ Episodic crises triggers include infection, dietary iron supplementation, menstruation ▪ Nocturnal hemoglobinuria (upon waking) ▪ Lumbar, abdominal, general musculoskeletal pain 194 OSMOSIS.ORG ▪ Splenomegaly may present in severe hemolysis setting ▪ Venous, arterial thrombosis DIAGNOSIS LAB RESULTS ▪ Normochromic, normocytic anemia; pancytopenia; ↑ lactate dehydrogenase (LDH) tests Sugar water test ▪ Serum mixed in sucrose (isotonic solution, low ionic strength) → predisposes to complement-mediated lysis → CD55/59deficient cells hemolyze Acid hemolysis test (Ham test) ▪ Alternative complement cascade triggered in acidified serum conditions → CD55/59deficient cells hemolyze CD55/59 protein flow cytometry ▪ Most sensitive, specific test TREATMENT MEDICATIONS ▪ Glucocorticoids (prednisone; typically poor response) ▪ Eculizumab: monoclonal antibody binds C5 cleavage → prevents MAC formation, complement-mediated cell lysis SURGERY ▪ Bone marrow transplantation